© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 13, 961,
July 4, 2001
© 2001 Oxford University Press
MEMORANDUM FOR: Science Writers and Editors on the Journal Press List
Genetic Modification of Cancer Cells Slows Blood Vessel Development
June 28, 2001 (EMBARGOED FOR RELEASE 4 P.M. EDT July 3)
New research shows that genetic manipulation of cancer cells may provide a means of slowing blood vessel development (angiogenesis) and inhibiting tumor growth.
Andrew Feldman, M.D., and Steven Libutti, M.D., working with their colleagues at the National Cancer Institute, Bethesda, Md., transferred the gene encoding the angiogenesis inhibitor endostatin into the mouse liver cell line NMuLi. Various tests proved that these modified cells produced endostatin in vivo and that tumor growth was inhibited. These results are presented in the July 4 issue of the Journal of the National Cancer Institute.
Inhibiting tumor angiogenesis is a promising new investigational strategy for treating cancer patients. However, there are difficulties in the manufacture, stability, and chronic administration of proteins that block blood vessel formation. Therefore, the authors used a retrovirus vector to introduce the endostatin gene into the NMuLi tumor cell line. Analysis of the fluid medium in which the gene-modified cells were grown confirmed that they were producing endostatin. Endostatin did not affect the growth of the modified cells. However, the endostatin produced in this manner did slow the growth of endothelial cells in laboratory cultures.
When mice were injected subcutaneously with NMuLi cells, they developed tumors that reached 2,400 mm3 in 63 days, whereas mice injected with modified NMuLi cells that produced endostatin had mean tumor volumes of less than 30 mm3. Mice that had unmodified NMuLi cells injected into their abdominal cavity had median survival times of 58 days, and all mice were dead by day 123. At this time, only 9% of the mice injected with modified NMuLi cells had died. Autopsies of mice that died revealed massive peritoneal tumor deposits and fluid build-up in the abdominal cavity. Surviving mice were killed and autopsied, which revealed only occasional, small peritoneal tumor deposits. Tumors derived from modified cells contained statistically significantly more endostatin than tumors grown from unmodified cells and had fewer developing blood vessels.
Endostatin appears to impart its antitumor effect solely by inhibiting angiogenesis, with minimal toxicity. Therefore, the authors conclude that their results provide the basis for further studies using retroviral endostatin gene transfer to treat cancer, including disseminated tumors of the peritoneal cavity.
In an editorial, Hynda K. Kleinman, Ph.D., and Gene Liau, Ph.D., say that the effectiveness of angiogenesis inhibitors as a cancer treatment remains to be determined. Although there have been promising results in animal studies, the human trials have been less successful. They note that the questions of how best to deliver the inhibitor, maintain its stability and activity, and target it to the tumor vasculature have not been answered. For many therapeutic indications, including antiangiogenesis gene therapy, the editorialists see a continued need for improved gene therapy vectors to overcome such problems as immune response to the vector, transduction efficiency, delivery of the gene to the target tissue, and controlled gene expression by the vector.
Contact: NCI Press Office, (301) 496-6641; fax 301-496-0846. (Note: The media contact for the paper and the editorial is the NCI Press Office because the authors are on the NCI staff.)
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Feldman AL, Alexander HR, Hewitt SM, Lorang D, Thiruvathukal CE, Turner EM, et al. Effect of retroviral endostatin gene transfer on subcutaneous and intraperitoneal growth of murine tumors. J Natl Cancer Inst 2001;93:1014–20.
Editorial: Kleinman HK, Liau G. Gene therapy for antiangiogenesis. J Natl Cancer Inst 2001;93:965–7.
Note: This memo to reporters is from the Journal staff and is not an official release of the National Cancer Institute (NCI) or Oxford University Press (OUP) nor does it reflect NCI or OUP policy. In addition, unless otherwise stated, all articles and items published in the Journal reflect the individual views of the authors and not necessarily the official points of view held by NCI, any other component of the U.S. government, OUP, or the organizations with which the authors are affiliated. Neither NCI nor any other component of the U.S. government nor OUP assumes any responsibility for the completeness of the articles or other items or the accuracy of the conclusions reached therein.
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